WO 95/10516, published Apr. 20, 1995 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or NR9 wherein R9 is Oxe2x88x92, xe2x80x94CH3 or xe2x80x94(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2; or
each of a, b, c, and d are independently selected from CR1 or CR2;
each R1 and each R2 is independently selected from H, halo, xe2x80x94CF3, xe2x80x94OR10 (e.g., xe2x80x94OCH3), xe2x80x94COR10, xe2x80x94SR10 (e.g., xe2x80x94SCH3 and xe2x80x94SCH2C6H5), xe2x80x94S(O)tR11 (wherein t is 0, 1 or 2, e.g., xe2x80x94SOCH3 and xe2x80x94SO2CH3), xe2x80x94SCN, xe2x80x94N(R10)2, xe2x80x94NR10R11, xe2x80x94NO2, xe2x80x94OC(O)R10, xe2x80x94CO2R10, xe2x80x94OCO2R11, xe2x80x94CN, xe2x80x94NHC(O)R10, xe2x80x94NHSO2R10, xe2x80x94CONHR10, xe2x80x94CONHCH2CH2OH, xe2x80x94NR10COOR11, 
xe2x80x83xe2x80x94SR11C(O)OR11 (e.g., xe2x80x94SCH2CO2CH3), xe2x80x94SR11N(R75)2 wherein each R75 is independently selected from H and xe2x80x94C(O)OR11 (e.g., xe2x80x94S(CH2)2NHC(O)O-t-butyl and xe2x80x94S(CH2)2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, xe2x80x94OR10 or xe2x80x94CO2R10:
R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III);
R5, R6, R7 and R8 each independently represents H, xe2x80x94CF3, xe2x80x94COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)tR11, xe2x80x94NR10COOR11, xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R11, xe2x80x94CO2R10, OPO3R10, or R5 is combined with R6 to represent xe2x95x90O or xe2x95x90S and/or R7 is combined with R8 to represent xe2x95x90O or xe2x95x90S;
R10 represents H, alkyl, aryl, or arallyl (e.g., benzyl);
R11 represents alkyl or aryl;
X represents N, CH or C, which C may contain an optional double bond (represented by the dotted line) to carbon atom 11:
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent xe2x80x94R10, halo, xe2x80x94OR11, xe2x80x94OCO2R11 or xe2x80x94OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR11)2: H and halo, dihalo, alkyl and H, (alkyl)2, xe2x80x94H and xe2x80x94OC(O)R10, H and xe2x80x94OR10, xe2x95x90O, aryl and H, xe2x95x90NOR10 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94 wherein p is 2, 3 or 4; and
W represents a group selected from the group consisting of: 
xe2x80x83wherein;
R12 is selected from the group consisting of: (a) H: (b) alkyl: (c) aralkyl (e.g., benzyl); and (d) heteroarylalkyl (heteroaralkyl) (e.g., xe2x80x94CH2-imidazolyl):
R13 and R14 are each independently selected from the group consisting of: (a) H; (b) xe2x80x94C(O)OR16 wherein R16 represents alkyl, aralkyl, and heteroaralkyl; (c) xe2x80x94SO2R17 wherein R17 is selected from the group consisting of; xe2x80x94NH2, xe2x80x94N(alkyl)2 wherein each alkyl is the same or different (e.g., xe2x80x94N(CH3)2), alkyl (e.g., C1-6 alkyl, such as methyl), aryl, aralkyl, heteroaryl and heteroaralkyl; (d) xe2x80x94C(O)R18 wherein R18 is selected from the group consisting of: aryl (e.g., phenyl), alkyl, aralkyl, heteroaryl, and heteroaralkyl; (e) C1-6 alkyl; (f) alkaryl; and (g) C3-6 cycloalkyl;
r is 0, 1 or 2;
s represents 1, 2, 3, 4, or 5 (preferably 3 or 4), and each Y for each xe2x80x94CY2xe2x80x94 group is independently selected from H or xe2x80x94OH, provided that both Y substituents of each xe2x80x94CY2xe2x80x94 group are not xe2x80x94OH, and provided that for the xe2x80x94CY2xe2x80x94 group alpha to the nitrogen both Y substituents are H, preferably each Y is H such that each xe2x80x94CY2xe2x80x94 group is a xe2x80x94CH2xe2x80x94 group, such that the group 
xe2x80x83forms a 3, 4, 5, 6, or 7 (preferably 5 or 6) membered ring (e.g., piperidyl or pyrrolidinyl),;
v is 0, 1 or 2;
R15 is selected from the group consisting of:
(a) heteroaryl (e.g., imidazolyl);
(b) a group selected from: 
(5) xe2x80x94CH(OCH2CH3)2,
(6) xe2x80x94OH, and
(7) xe2x80x94CN; and
(c) heterocycloalkyl selected from the group consisting of: 
z is 0, 1, 2, 3, 4, or 5 wherein each xe2x80x94CH2xe2x80x94 group is optionally substituted with a xe2x80x94OH group, i.e., each H of each xe2x80x94CH2xe2x80x94 group can optionally be replaced with a xe2x80x94OH group and the optional substitution on each xe2x80x94CH2xe2x80x94 group is independent of the substitution on any other xe2x80x94CH2xe2x80x94 group, generally each xe2x80x94CH2xe2x80x94 is unsubstituted;
R22 represents a group selected from: 
(5) alkyl (e.g., xe2x80x94CH3),
(6) xe2x80x94OR23 wherein R23 is selected from the group consisting of: alkyl, aryl and H, and 
xe2x80x83wherein R24 and R25 are independently selected from the group consisting of: xe2x80x94NH2, alkoxy (e.g., xe2x80x94OCH3), xe2x80x94OH, xe2x80x94CH2CO2H, xe2x80x94OCH2Ph (i.e., xe2x80x94OCH2C6H5), xe2x80x94CH(OCH3)CH(CH3)2 
xe2x80x83alkyl, aryl, H, aralkyl, and heteroaralkyl; or R24 and R25 taken together form a carbon chain having 4 or 5 (xe2x80x94CH2xe2x80x94) groups such that R24 and R25 taken together with the nitrogen to which they are bound form a 5 or 6 membered heterocycloalkyl ring.
The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene: (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
As used herein, the following terms are used as defined below unless otherwise indicated:
Acxe2x80x94represents acetyl;
MH+xe2x80x94represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
M+xe2x80x94represents the molecular ion of the molecule in the mass spectrum;
benzotriazol-1-yloxy represents 
1-methyl-tetrazol-5-ylthio represents 
alkenylxe2x80x94represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms;
alkynylxe2x80x94represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms;
alkylxe2x80x94(including the alkyl portions of aralkyl and heteroarylalkyl)xe2x80x94represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
aralkylxe2x80x94represents an aryl group, as defined below, bound to an alkyl group, as defined above, preferably the alkyl group is xe2x80x94CH2xe2x80x94, (e.g., benzyl);
aryl (including the aryl portion of aralkyl and aralkyl)xe2x80x94represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring) with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, xe2x80x94COOOR10 or xe2x80x94NO2;
BOCxe2x80x94represents xe2x80x94C(O)OC(CH3)3;
xe2x80x94CH2-imidazolyl represents an imidazolyl group bound by any substitutable carbon of the imidazole ring to a xe2x80x94CH2xe2x80x94, that is: 
xe2x80x83such as xe2x80x94CH2-(2-, 4- or 5-)imidazolyl, for example 
Etxe2x80x94represents ethyl;
haloxe2x80x94represents fluoro, chloro, bromo and iodo;
heteroarylxe2x80x94represents cyclic groups, optionally substituted with R3, R4, phenyl, and or xe2x80x94CH2C(O)OCH3, said cyclic groups having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic hetero cyclic groups preferably containing from 2 to 14 carbon atoms, e.g., (2-, 4- or 5-)imidazolyl, triazolyl, 
xe2x80x832-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), wherein pyridyl N-oxide can be represented as: 
heteroarylalkyl (heteroaralkyl)xe2x80x94represents a heteroaryl group, as defined above, bound to an alkyl group, as defined above, preferably the alkyl group is xe2x80x94CH2xe2x80x94 (e.g., xe2x80x94CH2-(4- or 5-)imidazolyl);
heterocycloalkylxe2x80x94represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR10xe2x80x94, suitable heterocycloalkyl groups include: (1) 2- or 3-tetrahydrofuranyl, (2) 2- or 3-tetrahydrothienyl, (3) 2-, 3- or 4-piperidinyl, (4) 2- or 3-pyrrolidinyl, (5) 2- or 3-piperizinyl, and (6) 2- or 4-dioxanyl; and
Phxe2x80x94represents phenyl
The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); isopropanol (iPrOH); ethanol (FtOH); methanol (MeOH): acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoro-acetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC): diisobutylaluminum hydride(DIBAL); and 4-methylmorpholine (NMM).
Reference to the position of the substituents R1, R2, R3, and R4 is based on the numbered ring structure: 
Those skilled in the art will also appreciate that the S and stereochemistry at the C-11 bond are: 
Compounds of Formula 1.0 include compounds wherein the bottom piperidinyl group is a 4- or 3-piperidinyl group, i.e., 
Compounds of Formula 1.0 include compounds wherein R2 and R4 are H, and R1 and R3 are halo (preferably independently selected from Br or Cl). For example, R1 is Br and R3 is Cl. These compounds include compounds wherein R1 is in the 3-position and R3 is in the 8-position, e.g., 3-Br and 8-Cl. Compounds of Formula 1.0 also include compounds wherein R2 is H, and R1, R3 and R4 are halo (preferably independently selected from Br or Cl).
Preferably, compounds of Formula 1.0 are represented by compounds of Formula 1.1: 
wherein all substituents are as defined for Formula 1.0.
Preferably, R2 is H and R1, R3 and R4 are halo; a is N and b, c and d are carbon; A and B are each H2; the optional bond between C5 and C6 is absent; X is CH; and R5, R6, R7 and R8 are H. More preferably, R1, R3 and R4 are independently selected from Br or Cl. Most preferably, R1 is Br, and R3 and R4 are independently selected from Cl and Br.
More preferably, compounds of Formula 1.0 are represented by compounds of Formula 1.2 and Formula 1.3: 
and most preferably, compounds of Formulas 1.4 and 1.5 
wherein R1, R3 and R4 are each independently selected from halo, preferably, Br or Cl; and A, B, X and W are as defined for Formula 1.0. More preferably, A and B are each H2; the optional bond between C5 and C6 is absent; and X is CH. Most preferably, R1 is Br; R3 and R4 are independently Br or Cl, and still more preferably R3 is Cl and R4 is Br; A and B are each H2; the optional bond between C5 and C6 is absent; X is CH; and R5, R6, R7 and R8 are H.
Examples of R15 include: 
When W represents: 
and r is 0: (1) preferably, R12 is selected from the group consisting of: (a) H; (b) alkyl; (c) aralkyl; and (d) heteroaralkyl; and most preferably, R12 is selected from the group consisting of: (a) H, (b) methyl, (c) xe2x80x94CH2-imidazolyl and (d) benzyl; (2) preferably, R13 and R14 are independently selected from the group consisting of: (a) H; (b) xe2x80x94C(O)OR16 wherein R16 is alkyl; (c) xe2x80x94SO2R17 wherein R17 is alkyl or aryl; (d) xe2x80x94C(O)R18 wherein R18 is aryl; and (e) alkyl; and most preferably, R13 and R14 are independently selected from the group consisting of: (a) H, (b) xe2x80x94C(O)OC(CH3)3, (c) xe2x80x94SO2CH3 and (d) xe2x80x94C(O)-phenyl. Preferably, when one of R13 or R14 is xe2x80x94C(O)OR16, xe2x80x94SO2R17, xe2x80x94C(O)R18, alkaryl or cycloalkyl, the remaining R13 or R14 is H. Preferred combinations of substituent groups include: (1) R12 being alkyl (more preferred, methyl), R13 being xe2x80x94C(O)OR16 (more preferred xe2x80x94C(O)OC(CH3)3) and R14 being H; (2) R12 being heteroarylalkyl (more preferred xe2x80x94CH2-(4 or 5)-imidazolyl), R13 being H or xe2x80x94C(O)OR16 (more preferred H or xe2x80x94C(O)OC(CH3)3) and R14 being H; (3) R12 being aralkyl (more preferred benzyl), R13 being xe2x80x94C(O)OR16 (more preferred xe2x80x94C(O)OC(CH3)3) and R14 being H; (4) R12 being H, R13 being xe2x80x94C(O)OR16 (more preferred xe2x80x94C(O)OC(CH3)3) and R14 being H; (5) R12 being H, R13 being xe2x80x94SO2R17 (more preferred xe2x80x94SO2CH3) and R14 being H; and (6) R12 being H, R13 being xe2x80x94C(O)R18 (more preferred xe2x80x94C(O)-phenyl) and R14 being H.
Those skilled in the art will appreciate that the W substituent described in the previous paragraph can be derived from known amino acids having one carboxyl and amino group. Examples of such amino acids include but are not limited to glycine, alanine, phenylalanine, asparagine and histidine. For example, see Morrison and Boyd, Organic Chemistry, Fifth Edition, Allyn and Bacon, Inc., Boston, pages 1346-1347, the disclosure of which is incorporated herein by reference thereto.
When W represents 
and r is 1 or 2, preferably R12 is H, and R13 and R14 are independently selected from alkyl, most preferably, R13 and R14 are the same alkyl group (e.g., methyl).
When W represents 
s is preferably 3, such that a pyrrolidone ring is formed, and R13 is preferably H or xe2x80x94C(O)OR16 wherein R16 is alkyl; most preferably, R13 is H or xe2x80x94C(O)OC(CH3)3.
When W represents: 
and v is 0, preferably R12 represents H and R15 represents heteroaryl or heterocycloalkyl. Most preferably, when R15 is heteroaryl said heteroaryl is imidazolyl 
and when R15 is heterocycloalkyl said heterocycloalkyl is 
When W represents: 
and v is 1 or 2, preferably R12 represents H and R15 is heterocycloalkyl. Most preferably R12 represents H and R15 is heterocycloalkyl, e.g., 
When W represents 
and z is 0, preferably R22 represents 
and R24 and R25 preferably represent H.
When W represents 
and z is 1, 2, 3, 4 or 5, R22 preferably represents xe2x80x94OR23 and R23 preferably represents alkyl and most preferably methyl.
Compounds of Formulas 1.2A and 1.3A: 
are preferred when X is CH or N, and R1, R3 and R4 are halo.
The preferred compounds of this invention are represented by the compounds of Formulas: 
wherein R1, R3 and R4 are halo and the remaining substituents are as defined above, with the compounds of Formula 1.5A being more preferred.
Those skilled in the art will appreciate that W substituent: 
wherein r is 0 includes 
and W substituent: 
wherein v is 0 includes 
Representative compounds of Formula 1.0 wherein W is 
and r is 0 include: 
Representative compounds of Formula 1.0 wherein W is 
and r is 1 or 2 include: 
Representative compounds of Formula 1.0 wherein W is 
and s is 3 include: 
Representative compounds of Formula 1.0 wherein W is 
and v is 0 include: 
Representative compounds of Formula 1.0 wherein W is 
and v is 1 include: 
Compounds of Formula 1.0 wherein W is 
and z is 0 include: 
Compounds of Formula 1.0 wherein W is 
and z is 1, 2, 3, 4 or 5 include: 
Compounds of this invention also include: 
or pharmaceutically acceptable salts or solvates thereof.
The compounds of this invention also include the 1-N-oxidesxe2x80x94i.e, for example, compounds of the the formula: 
wherein  represents the remainder of the compound, or pharmaceutically acceptable salts or solvates thereof.
Optical rotation of the compounds ((+)- or (xe2x88x92)-) are measured in methanol or ethanol at 25xc2x0 C.
This invention includes the above compounds in the amorphous state or in the cyrstalline state.
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the present invention may exist in different isomeric forms (e.g., enantiomers or diastereoisomers) including atropisomers (i.e., compounds wherein the 7-membered ring is in a fixed conformation such that the 11-carbon atom is positioned above or below the plane of the fused benzene rings due to the presence of a 10-bromo substituent). The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold, silver and lithium salts. For example, compounds having the xe2x80x94OR23 group wherein R23 is H can form a sodium or lithium saltxe2x80x94i.e., a compound with a xe2x80x94ONa or xe2x80x94OLi group. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention may be prepared according to the procedures described in WO 95/10516 published Apr. 20, 1995, application Ser. No. 08/410,187 filed Mar. 24, 1995, application Ser. No. 08/577,951 filed Dec. 22, 1995 (now abandoned), application Ser. No. 08/615,760 filed Mar. 13, 1996 (now abandoned), WO 97/23478 published Jul. 3, 1997 which discloses the subject matter of Ser. No. 08/577,951 and 08/615,760, application Ser. No. 08/710,225 filed Sep. 13, 1996, and application Ser. No. 08/877,453 filed Jun. 17, 1997; the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.
Compounds of the invention can be prepared by reacting a compound of the formula: 
wherein all substituents are as defined for Formula 1.0, with the appropriate protected piperidinyl acetic acid (e.g., 1-N-t-butoxycarbonylpiperidinyl acetic acid together with DEC/HOBT/NMM in DMF at about 25xc2x0 C. for about 18 hours to produce a compound of the formula: 
The compound of Formula 21.0 is then reacted either with TFA or 10% sulfuric acid in dioxane and methanol followed by NaOH to produce the compound of Formula 20.0 
For example, the compound of formula 
can be prepared by reaction of a compound of Formula 19.0 with 1-N-t-butoxy-carbonylpiperidinyl-4-acetic acid as described above.
For example, compounds of Formula 22.0 include the compounds: 
The preparation of these compounds are described in Preparative Examples 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13, respectively, below.
The compounds of the invention can be prepared by reacting a compound of the formula: 
with the appropriate protected piperidinyl acetic acid (e.g., 1-N-t-butoxycarbonylpiperidinyl acetic acid together with DEC/HOBT/NMM in DMF at about 25xc2x0 C. for about 18 hours to produce a compound of the formula: 
The compound of Formula 21.1 is then reacted either with TFA or 10% sulfuric acid in dioxane and methanol followed by NaOH to produce the compound of Formula 22.1 
The amide compounds of this invention, represented by Formula 1.7 
can be prepared by reacting the compound of Formula 22.1 with the appropriate carboxylic acid in the presence of a coupling agent such as DEC and HOBT in dimethylformamide. Alternatively, the compound of Formula 22.1 can be reacted with an acid chloride or anhydride in a solvent such as pyridine.
The W group on Formula 1.7 can contain functionality that can be converted to other functionality by methods, such as hydrolysis, that are well known in the art. For example, the compound of Formula 16.0-B, can be converted to the compound of Formula 74-B, and the compound of Formula 35.0-B to the compound of Formula 52.0-B by treatment with methanolic potassium hydroxide followed by acid. Also, compounds of Formulas 86.0-B and 89.0-B can be converted to compounds of Formulas 88.0-B and 90.0-B, respectively, by treatment with acids such as trifluoroacetic acid or dioxane saturated with HCl gas.
Compounds having an 1-Nxe2x80x94O group: 
can be prepared from the corresponding pyridyl compounds: 
by oxidation with meta-chloroperoxybenzoic acid. This reaction is conducted in a suitable organic solvent, e.g., dichloromethane (usually anhydrous) or methylene chloride, at a suitable temperature, to produce the compounds of the invention having the Nxe2x80x94O substituent at position 1 of Ring I of the tricyclic ring system.
Generally, the organic solvent solution of the starting tricyclic reactant is cooled to about 0xc2x0 C. before the m-chloroperoxybenzoic acid is added. The reaction is then allowed to warm to room temperature during the reaction period. The desired product can be recovered by standard separation means. For example, the reaction mixture can be washed with an aqueous solution of a suitable base, e.g., saturated sodium bicarbonate or NaOH (e.g., 1N NaOH), and then dried over anhydrous magnesium sulfate. The solution containing the product can be concentrated in vacuo. The product can be purified by standard means, e.g., by chromatography using silica gel (e.g., flash column chromatography).
Alternatively, Nxe2x80x94O compounds can be made from intermediate: 
by the above oxidation procedure with m-chloroperoxybenzoic acid and 
wherein Q is a protecting group, e.g., BOC. After oxidation the protecting group is removed by techniques well known in the art. The Nxe2x80x94O intermediate is then reacted further to produce the compounds of the invention.
Compounds of Formula 19.0 include the compound of Formula 19.1: 
The compound of Formula 19.1 is prepared by methods known in the art, for example by methods disclosed in WO 95/10516, in U.S. Pat. No. 5,151,423 and those described below. The above intermediate compound can also be prepared by a procedure comprising the following steps:
(a) reacting an amide of the formula 
wherein R11a is Br, R5a is hydrogen and R6a is C1-C6 alkyl, aryl or heteroaryl; R5a is C1-C6 alkyl, aryl or heteroaryl and R6a is hydrogen; R5a and R6a are independently selected from the group consisting of C1-C6 alkyl and aryl; or R5a and R6a, together with the nitrogen to which they are attached, form a ring comprising 4 to 6 carbon atoms or comprising 3 to 5 carbon atoms and one hetero moiety selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94NR9axe2x80x94, wherein R9a is H, C1-C6 alkyl or phenyl;
xe2x80x83with a compound of the formula 
wherein R1a, R2a, R3a and R4a are independently selected from the group consisting of hydrogen and halo and R7a is Cl or Br, in the presence of a strong base to obtain a compound of the formula 
(b) reacting a compound of step (a) with
(i) POCl3 to obtain a cyano compound of the formula 
(ii) DIBALH to obtain an aldehyde of the formula 
(c) reacting the cyano compound or the aldehyde with a piperidine derivative of the formula 
wherein L is a leaving group selected from the group consisting of Cl and Br, to obtain a ketone or an alcohol of the formula below, respectively: 
(d)(i) cyclizing the ketone with CF3SO3H to obtain a compound of Formula 13.0a wherein the dotted line represents a double bond; or
(d)(ii) cyclizing the alcohol with polyphosphoric acid to obtain an Intermediate compound wherein the dotted line represents a single bond.
Methods for preparing the Intermediate compounds disclosed in WO 95/10516, U.S. Pat. No. 5,151,423 and described below employ a tricyclic ketone intermediate. Such intermediates of the formula 
wherein R11b, R1a, R2a, R3a and R4a are independently selected from the group consisting of hydrogen and halo, can be prepared by the following process comprising:
(a) reacting a compound of the formula 
(i) with an amine of the formula NHR5aR6a, wherein R5a and R6a are as defined in the process above; in the presence of a palladium catalyst and carbon monoxide to obtain an amide of the formula: 
(ii) with an alcohol of the formula R10aOH, wherein R10a is C1-C6 lower alkyl or C3-C6 cycloalkyl, in the presence of a palladium catalyst and carbon monoxide to obtain the ester of the formula 
xe2x80x83followed by reacting the ester with an amine of formula NHR5aR6a to obtain the amide;
(b) reacting the amide with an iodo-substituted benzyl compound of the formula 
wherein R1a, R2a, R3a, R4a and R7a are as defined above, in the presence of a strong base to obtain a compound of the formula 
(c) cyclizing a compound of step (b) with a reagent of the formula R8aMgL, wherein R8a is C1-C8 alkyl, aryl or heteroaryl and L is Br or Cl, provided that prior to cyclization, compounds
wherein R5a or R6a is hydrogen are reacted with a suitable N-protecting group.
(+)-Isomers of compounds of Formula 19.2 
can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of Formula 19.3 
is reacted with an enzyme such as Toyobo LIP-300 and an acylating agent such as trifluoroethyl isobutyrate; the resultant (+)-amide is then isolated from the (xe2x88x92)-enantiomeric amine by techniques well known in the art, and then the (+)-amide is hydrolyzed, for example by refluxing with an acid such as H2SO4, and the resulting compound is then reduced with DIBAL by techniques well known in the art to obtain the corresponding optically enriched (+)-isomer of Formula 19.2. Alternatively, a racemic compound of Formula 19.3, is first reduced to the corresponding racemic compound of Formula 19.2 and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer.
Those skilled in the art will appreciate that compounds of Formula 1.0 having other R1, R2, R3 and R4 substituents may be made by the above enzyme process.
To produce the compounds of Formula 1.0, wherein W is 
r is 0, and R13 and R14 are selected from H or xe2x80x94C(O)OR16, the compounds of Formulas 20.0 or 22.0 are reacted with the appropriate protected amino acid: 
in the presence of DEC and HOBt in dimethylformamide to produce a compound of the formula: 
respectively.
Reaction of compounds of Formulas 23.0 or 24.0 with TFA in methylene chloride results in the deprotected compounds: 
respectively.
Compounds of Formula 1.0 wherein W is 
r is 0, R12 is H, R13 or R14 is H, and the remaining R13 or R14 is xe2x80x94C(O)OR16 can be prepared by reacting a compound of Formula 1.0 wherein W is 
r is 0, R12 is H, and R13 and R14 are both H, with the appropriate chloroformate 
TEA and CH2Cl2.
Compounds of Formulas 25.0 or 26.0 wherein R13 is selected from xe2x80x94SO2R17 or xe2x80x94C(O)R18 can be prepared by reacting a compound of Formula 25.0 or 26.0 with a suitable sulfonyl chloride (R17SO2Cl) or a suitable acyl chloride (R18C(O)Cl) with TEA in a suitable organic solvent (e.g., CH2Cl2).
Compounds of Formula 1.0 wherein W is 
r is 1 or 2 and R12 is H can be prepared by reacting a compound of Formula 20.0 or 22.0 with the appropriately substitued carboxylic acid and, for example DEC, HOBT and N-methylmorpholine, or by reacting a compound of Formula 20.0 or 22.0 with the appropriately substituted acid chloride.
For example, a compound of Formula 20.0 or 22.0 can be reacted with 
from propionic acid, wherein R13 and R14 are, for example, alkyl (e.g., methyl). Where the amino carboxylic acid is not commercially available, it can be prepared by reaction of ethyl acrylate with the appropriate amino compound (as described by Ahn, K. H. et al., Tetrahedron Letters , 35, 1875-1878 (1994)) with subsequent hydrolysis of the ester to the desired aminocarboxylic acid.
Also, for example, a compound of Formula 20.0 or 22.0 can be reacted with 
from butyric acid, wherein R13 and R14 are, for example, alkyl (e.g., methyl). Where the amino carboxylic acid is not commercially available, the appropriate acid chloride can be prepared in a manner similar to that described by Goel, O. P. et al., Synthesis, p. 538 (1973). The acid chloride is then reacted with a compound of Formula 20.0 or 22.0 to give the compound 
respectively. The chloro atom can then be displaced with the appropriate amine to give the desired compound.
Where either R13 or R14 is H, then the starting material would be a protected amino carboxylic acid 
wherein Z is an appropriater protecting group (e.g., BOC, CBZ (carbonylbenzyloxy) or TFA). Coupling this protected amino carboxylic acid with a compound of Formula 20.0 or 22.0 would then give the amino protected intermediate 
respectively. The amino protected intermediate (20.0B or 22.0B) would then be alkylated, and then the protecting group removed, using standard procedures known in the art.
Compounds of Formula 1.0 wherein W is 
v is 0, and R12 is H can be prepared by reacting a compound of Formula 20.0 or 22.0 with chloroacetylchloride, TEA and CH2Cl2 to produce a compound of the formula: 
The chloro atom in the xe2x80x94C(O)CH2Cl group in the compound of Formula 26.0 or 27.0 is then displaced with an appropriate nucleophile, R15, using a suitable base, e.g., sodium carbonate, and optionally, a suitable suitable solvent (e.g., DMF).
Compounds of Formula 1.0 wherein W is 
z is 0, and R22 is 
can be prepared from compounds of Formula 20.0 or 22.0 by reaction with oxallyl chloride and an excess of the amine 
Compounds of Formula 1.0 wherein W is 
z is 1, 2, 3, 4 or 5 and R22 is xe2x80x94OR23, and R23 is, for example, alkyl, can be prepared by reaction of a compound of Formula 20.0 or 22.0 with the appropriate substituted dicarboxylic acid which is protected as a mono ester with an appropriate alkyl or aryl group. The corresponding acids (i.e., R23 is H) can be obtained by base hydrolysis (e.g., NaOH) of the ester. The compounds, wherein R22 is xe2x80x94NR24R25, can be prepared by reacting the appropriately substituted amine with the carboxylic acid generated above using DEC, HOBT and NMM. For example, for compounds wherein z is 3 a glutarate 
(wherein R23 is alkyl, e.g., methyl) can be used, and for compounds wherein z is 2 a succinate 
(wherein R23 is alkyl, e.g., methyl) can be used, and for compounds wherein z is 1 a malonate 
(wherein R23 is alkyl, e.g., ethyl) can be used.
Reaction Scheme 1 illustrates the preparation of compounds of this invention. 